Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is the predominant cause of dementia in people over 65 years of age. AD is characterized neuropathologically by significant neuronal cell loss in certain brain areas, an abundance of structures resembling neurons containing intracellular paired helical filaments (referred to as neurofibrillary tangles), and by the extracellular deposition of a proteinacious material in the brains of AD patients referred to as either neuritic/Aβ plaques or diffuse/Aβ deposits. The major protein component of neuritic/Aβ plaques and diffuse/Aβ deposits is a specific peptide alloform of Aβ known as Aβ42. Increased accumulation of Aβ42 has been postulated to significantly contribute to the pathogenesis of AD, and is also associated with various other cerebral amyloidoses and neurological disorders such as Down's syndrome (DS), Hereditary Cerebral Hemorrhage with Amyloidosis-Dutch Type (HCHWA-D), cerebral amyloid angiopathy (CAA), and mild cognitive impairment (MCI).
One of the most important lines of evidence implicating the accumulation of the Aβ42 peptide in AD comes from the identification of various mutations that result in increased formation of Aβ42 and account for certain types of inherited AD (familial AD, or FAD). FAD individuals comprise <10% of all AD cases and generally exhibit symptoms of the disease much earlier than sporadic AD patients.
All Aβ peptides are derived from proteolytic processing of an amyloid precursor protein (APP). mRNA generated from the APP gene on chromosome 21 undergoes alternative splicing to yield several isoforms, three of which (APP695, 751, and 770 amino acid isoforms) predominate in the brain and the cerebrovasculature. The major APP isoforms are single-transmembrane proteins, composed of an extracellular amino-terminal domain (596-687 amino acids) and cytoplasmic tail containing an intracellular trafficking signal (approximately 80-99 amino acids). Within APP, the Aβ peptide sequence is located partially on the extracellular side of the membrane and extends partially into the transmembrane region.
APP is trafficked through the constitutive secretory pathway, where it undergoes post-translational processing, including proteolysis via either of two distinct processing pathways, an amyloidogenic pathway or an alternate pathway. In the amyloidogenic pathway, APP is cleaved by either β-secretase-1 (RACE-1) or Cathepsin D at the beginning of the Aβ domain that defines the amino terminus of all full length Aβ peptides. These Aβ peptides vary in length from approximately 34-42 amino acids. Cleavage of APP by either BACE-1 or Cathepsin D generates a soluble amino-terminal fragment, sAPPβ, as well as an amyloidogenic carboxyl-terminal fragment approximately 99 amino acids long referred to as (C99). Additional proteolysis of C99 by γ-secretase, a presenilin-dependent proteolytic complex, produces an intracellular domain referred to as AICD and number of different Aβ peptides of various lengths (e.g., Aβ34, Aβ37, Aβ38, Aβ39, Aβ40 and Aβ42). In another processing pathway, APP is cleaved by α-secretase within the Aβ domain, yielding a soluble amino-terminal fragment, sAPPα, and a carboxyl-terminal fragment approximately 83 amino acids long referred to as C83. This α-secretase-mediated proteolysis of APP precludes the formation of the intact full length Aβ peptides (e.g., Aβ34, Aβ37, Aβ38, Aβ39, Aβ40 and Aβ42) which specifically require the combination of either BACE-1 or Cathepsin D and γ-secretase activities on APP and C99, respectfully.
The predominant Aβ peptide alloform found in neuritic/Aβ plaques and diffuse/Aβ deposits from AD brains is the Aβ42 peptide. Aβ42 is the species initially deposited in AD brains and is highly prone to aggregate in vitro. Therefore, enzymes responsible for generating the Aβ42 species in particular, may be a viable target in the development of therapeutics for the treatment of disease or disorders characterized by excessive Aβ42 generation and/or accumulation (Selkoe, D J Alzheimer's disease: genes, proteins and therapy [review] Physiol. Rev. 2001; 81:741-766).
Currently, there is no cure or effective treatment for preventing or retarding the progression of AD pathogenesis, and the few FDA-approved drugs, including Aricept, Exelon, Cognex, Reminyl and Memantine, are palliative treatments at best. Based on the well established correlation between cerebral Aβ42 accumulation and neuronal cell loss in AD; attenuating Aβ42 levels relative to the levels of shorter Aβ peptide species, and thereby preferentially reducing the levels of the putatively pathogenic Aβ42 species, represents a rational approach for decreasing extracellular Aβ42 deposition (thereby attenuating formation of diffuse Aβ deposits as well as neuritic/Aβ plaques) and minimizing neuronal cell death in AD.
There exists a medical need for compounds that modulate levels of Aβ peptides, including Aβ42. Such compounds should be useful for the treatment of a variety of degenerative disorders, including neurodegenerative diseases such as AD (Imbimbo, B P Therapeutic potential of gamma-secretase inhibitors and modulators Curr Top Med Chem 2008; 8:54-61).
Compounds of the invention are especially advantageous because they are expected to display an improved facility to achieve beneficial levels in the brain of a subject administered the compound compared to previously described compounds of this general class (U.S. Pat. No. 7,244,739—Compounds and uses thereof in modulating amyloid beta 2007 US Patent Office). The novel compounds described herein, especially those containing the cleavable phosphonomethoxy moiety, should be much more amenable to preclinical and clinical development protocols as a result of their significant solubilities in aqueous solvents.